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Title: Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells

Abstract

Organophosphorus compounds (OP) such as phenyl saligenin phosphate (PSP) and mipafox (MPX) which cause delayed neuropathy, inhibit neuropathy target esterase (NTE), while OPs such as paraoxon (PXN) react more readily with acetylcholinesterase. In yeast and mammalian cell lines, NTE has been shown to have phospholipase B (PLB) activity which deacylates intracellular phosphatidylcholine to glycerophosphocholine (GroPCho) and can be detected by metabolic labeling with [{sup 14}C]choline. Here we investigated PLB activity in primary cultures of mouse neural cells. In cortical and cerebellar granule neurons and astrocytes, [{sup 14}C]GroPCho labeling was inhibited by PSP and MPX: phenyl dipentylphosphinate (PDPP), a non-neuropathic NTE inhibitor, was more potent, while PXN, was substantially less so. In all three cell types, conversion of [{sup 14}C]phosphatidylcholine to [{sup 14}C]GroPCho over 24 h was relatively small (2.3-14%). Consequently, even with > 80% inhibition of [{sup 14}C]GroPCho production, increased [{sup 14}C]phosphatidylcholine was not detected. At concentrations of 1-10 {mu}M, only PSP was cytotoxic to cortical and cerebellar granule neurons after 24-h exposure. Moreover, dramatic changes in glial cell morphology were induced by PSP, but not PDPP or MPX, with rapid (2-3 h) rounding up of astrocytes and of Schwann cells in cultures of dissociated mouse dorsal root ganglia. Wemore » conclude that PLB activity is present in a variety of cultured mouse neural cell types but that acute loss of this activity is not cytotoxic. Conversely, the rapid toxic effects of PSP in vitro suggest that a serine hydrolase distinct from NTE is required continuously by neurons and glia.« less

Authors:
 [1];  [1];  [1];  [1];  [2]
  1. MRC Toxicology Unit, University of Leicester, LE1 9HN (United Kingdom)
  2. MRC Toxicology Unit, University of Leicester, LE1 9HN (United Kingdom). E-mail: pg8@le.ac.uk
Publication Date:
OSTI Identifier:
20976884
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 219; Journal Issue: 2-3; Other Information: DOI: 10.1016/j.taap.2006.08.002; PII: S0041-008X(06)00268-7; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARBON 14; CHOLINE; GANGLIONS; GROWTH FACTORS; IN VITRO; LABELLING; LECITHINS; MICE; MORPHOLOGY; NERVE CELLS; PHOSPHATES; ROOTS; SERINE; TOXICITY; YEASTS

Citation Formats

Read, David J., Langford, Lynda, Barbour, Helen R., Forshaw, Philip J., and Glynn, Paul. Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.08.002.
Read, David J., Langford, Lynda, Barbour, Helen R., Forshaw, Philip J., & Glynn, Paul. Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells. United States. doi:10.1016/j.taap.2006.08.002.
Read, David J., Langford, Lynda, Barbour, Helen R., Forshaw, Philip J., and Glynn, Paul. Thu . "Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells". United States. doi:10.1016/j.taap.2006.08.002.
@article{osti_20976884,
title = {Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells},
author = {Read, David J. and Langford, Lynda and Barbour, Helen R. and Forshaw, Philip J. and Glynn, Paul},
abstractNote = {Organophosphorus compounds (OP) such as phenyl saligenin phosphate (PSP) and mipafox (MPX) which cause delayed neuropathy, inhibit neuropathy target esterase (NTE), while OPs such as paraoxon (PXN) react more readily with acetylcholinesterase. In yeast and mammalian cell lines, NTE has been shown to have phospholipase B (PLB) activity which deacylates intracellular phosphatidylcholine to glycerophosphocholine (GroPCho) and can be detected by metabolic labeling with [{sup 14}C]choline. Here we investigated PLB activity in primary cultures of mouse neural cells. In cortical and cerebellar granule neurons and astrocytes, [{sup 14}C]GroPCho labeling was inhibited by PSP and MPX: phenyl dipentylphosphinate (PDPP), a non-neuropathic NTE inhibitor, was more potent, while PXN, was substantially less so. In all three cell types, conversion of [{sup 14}C]phosphatidylcholine to [{sup 14}C]GroPCho over 24 h was relatively small (2.3-14%). Consequently, even with > 80% inhibition of [{sup 14}C]GroPCho production, increased [{sup 14}C]phosphatidylcholine was not detected. At concentrations of 1-10 {mu}M, only PSP was cytotoxic to cortical and cerebellar granule neurons after 24-h exposure. Moreover, dramatic changes in glial cell morphology were induced by PSP, but not PDPP or MPX, with rapid (2-3 h) rounding up of astrocytes and of Schwann cells in cultures of dissociated mouse dorsal root ganglia. We conclude that PLB activity is present in a variety of cultured mouse neural cell types but that acute loss of this activity is not cytotoxic. Conversely, the rapid toxic effects of PSP in vitro suggest that a serine hydrolase distinct from NTE is required continuously by neurons and glia.},
doi = {10.1016/j.taap.2006.08.002},
journal = {Toxicology and Applied Pharmacology},
number = 2-3,
volume = 219,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}